Abstract Opioid drugs like morphine, codeine, and fentanyl confer life-saving analgesia for millions, enabling otherwise impossible medical interventions. These benefits are offset by dose limiting liabilities, including respiratory depression - the cause of all opioid deaths - and opioid use disorder (OUD). OUD reflects a cycle of increasing use, dependence, and withdrawal that eventually triggers a respiratory crisis. The CDC estimates that 72,000 Americans died in opioid overdose last year, the leading cause of death in adults under 50. Many of these deaths arise from overdoses (OD) of potent opioids like fentanyl and carfentanyl. While naloxone can restore breathing, its short half-life requires multiple administrations to reverse OD, and may result in relapse after initial reversal, as naloxone is eliminated while the illicit drug persists. Further, the anguish of precipitated withdrawal prompts rapid, and exceedingly dangerous, return to drug-seeking. Beyond OD reversal, the standard of care in OUD is maintenance treatment with agonists buprenorphine and methadone. Both reduce relapses and mortality, but access and adoption are limited by dosage forms, metabolic liabilities, and potential for abuse and diversion. Better medicines for overdose reversal and for OUD maintenance are urgently needed. Here we develop chemically novel, potent mu-opioid receptor (MOR) antagonists, low- and mid-efficacy partial agonists. Our current lead counds can outcompete opioid overdoses in preclinical models with a longer half-life, a key naloxone liability. The potent, low-efficacy partial agonists add a low opioid tone, diminishing the aversive effects of pure antagonists. These, and the mid-efficacy partial agonists, are leads to maintenance therapeutics for OUD.